6-substituted-4-dialkylaminotetrahydrobenz(c,d)indoles

ABSTRACT

(±)-4-substitutedamino-6-alkoxy, benzyloxy, acyloxy, or hydroxy-1,3,4,5-tetrahydrobenz[c,d]indoles, pharmaceutically acceptable salts thereof are, anti-depressants.

CROSS-REFERENCE

This application is a division of application Ser. No. 06/697,310 filedFeb. 1, 1985, U.S. Pat. No. 4,983,622, which is a continuation-in-partof Ser. No. 06/577,096 filed Feb. 6, 1984, now abandoned.

BACKGROUND OF THE INVENTION

The benz[c,d]indole ring system (I) has been known since 1949. ##STR1##For example Uhle et al. J. Am. Chem. Soc., 71, 1611 (1949); ibid, 73,2402 (1951); Grob et al. Helv. Chim. Acta., 33, 1796, 1955 (1950), 35,2095 (1952), 36, 839 (1953) and Stoll et al. ibid, 33, 2254, 2257(1950); 35, 148 (1952), prepared, among other compounds, a5-keto-1,3,4,5-tetrahydrobenz[c,d]indole plus the corresponding 4-aminoand 4-acetylamino derivatives. A useful starting material for thesynthesis of these compounds was a 1-benzoyl-1,2,2a,3,4,5-hexahydroderivative, II. ##STR2## formed by the ring closure of1-benzoyl-2(3-indolinyl)-propionylchloride under Friedel-Craftsconditions. Kornfeld et al., J.A.C.S., 78, 3087 (1956) also preparedthis compound and converted it, via a series of intermediates, to the4-amino-5-keto derivative which was, in itself, a key intermediate inthe first total synthesis of lysergic acid. In this synthetic procedure,a fourth ring (an N-methyl piperidine ring) was grafted onto anappropriately substituted tricyclic1,2,2a,3,4,5-hexahydrobenz[c,d]indole. Stoll et al. Helv. Chim. Acta,35, 148 (1952) also prepared(±)-4-dimethylamino-1,3,4,5-tetrahydrobenz[c,d]indole. Bach andKornfeld, U.S. Pat. No. 4,110,339, prepared the corresponding4-di-n-propylamino compound. Ledelec et al, U.S. Pat. No. 4,447,438discloses 4-piperidyl-substituted-1H-indole having dopaminergicproperties.

Certain naturally occurring alkaloids, agroclavine and elymoclavine,have been converted by Cassady et al. J. Med. Chem. , 17, 300 (1974) toN-methyldioxychanoclavine, N-methylchanoclavine, and chanoclavine, all4,5-disubstituted tetrahydrobenz[c,d]indoles (III). ##STR3## wherein Xis H or OH and R¹ is CH₃ or H. Compounds according to III were withoutsignificant prolactin inhibiting activity, unlike the Bach-Kornfeld(±)-4-di-n-propylamino-1,3,4-5-tetrahydrobenz[c,d]indole, which wasfound to be a selective dopamine agonist as shown by its action ininhibiting dopamine uptake in vitro in bovine striatal membrane Thecorresponding 4-(dimethyl)amino derivative of Stoll et al. (loc. cit.)was used only as an intermediate. The 4-aminotetrahydrobenz[c,d]indolesand related derivatives are weak serotonin antagonists with oneexception, the 4-acetylamino-5-oxo derivative--see Harris and Uhle, J.Pharm. & Exper. Therap., 128, 358 (1960).

SUMMARY OF THE INVENTION

This invention provides4-aminosubstituted-6-substituted-1,3,4,5-tetrahydrobenz[c,d]indoles ofthe formula ##STR4## wherein R¹ and R² are individually hydrogen,methyl, ethyl, n-propyl or allyl, and X is an OH, OC₁₋₃ alkyl, O-benzyl,or O-acyl; and pharmaceutically acceptable salts thereof.

Illustrative of those groups which NR¹ R² represents are included amino,methylamino, n-propylamino, ethyl-n-propylamino, diethylamino,ethylamino, n-propylamino and the like. The term "C₁₋₃ alkyl" as usedherein includes the methyl, ethyl, n-propyl and isopropyl radicals. Theterm "acyl" includes groups derived from both carboxylic and sulfonicacids; i.e., groups of the general structure R³ Z wherein Z is CO or SO₂[indicating radicals derived from carboxylic (COOH) or sulfonic (SO₂ OH)acids] and R3 is C₁₋₃ alkyl, C₃₋₈ cycloalkyl, phenyl, naphthyl andsubstituted phenyl wherein said substituents can be 1 or 2 members ofthe group halogen (Cl, Br, F), C₁₋₂ alkyl, C₁₋₂ alkyloxy or otherbiologically inert substituent. Illustrative acyl moieties includebenzoyl, p-tosyl, acetyl, propionyl, isobutyryl, mesyl, ethylsulfonyl,n-propylsulfonyl, p-chlorobenzenesulfonyl, 3,4-methylenedioxybenzoyl,anisoyl, ethoxy-benzensulfonyl, 2,4-xylylsulfonyl,3,4-dichlorobenzenesulfonyl, cyclopropylcarbonyl, cyclobutylsulfonyl,cycloheptylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl,cyclopentylcarbonyl, α-naphthoyl, β-naphthoyl, α-naphthylsulfonyl,β-naphthylsulfonyl, and the like groups. Since the O-acylatedderivatives of IV above are chiefly useful as intermediates, or in someinstances, as prodrugs, it will be apparent to those skilled in the artthat other acyl groups than those enumerated above can function in anequivalent manner to protect the free OH group.

Compounds according to IV in which X is O--C₁₋₃ alkyl are, in addition,useful intermediates for preparing other compounds coming within thescope of this invention.

Pharmaceutically-acceptable acid addition salts of the compounds of thisinvention include salts derived from non-toxic inorganic acids such as:hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid,hydrobromic acid, hydriodic acid, phosphorus acid and the like, as wellas salts derived from non-toxic organic acids such as aliphatic mono anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoicand hydroxyalkandioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, etc. Such pharmaceutically-acceptable salts thus includesulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,caprylate, acrylate, formate, isobutyrate, caprate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, mandelate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, phthalate, terephthalate, benzenesulfonate,toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate,phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,β-hydroxybutyrate, glycollate, malate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mesylate and the like salts.

The compounds of formula IV are central serotonin agonists, useful asanti-depressants. Thus, included within the present invention is apharmaceutical formulation which comprises as an active ingredient acompound of formula IV, or a pharmaceutically-acceptable salt thereof,associated with one or more pharmaceutically-acceptable carriers orexcipients therefor. The formulation, or the active ingredient thereof,can be used as a method of treating depression, obesity, alcoholism,smoking, or senile dementia in a warm-blooded animal by administering tosaid animal a therapeutically-effective amount of a compound of formulaIV, or a pharmaceutically-acceptable acid addition salt thereof.

Compounds according to formula IV have an asymmetric center at C-4 andthus occur as a (±)- or dl racemic mixture. This invention includes bothstereoisomers represented by formula IV. The individual stereoisomerscan be prepared by resolving a racemate of a 2,2a-dihydro indoleintermediate (XIV, XIVa, XV, XVa, XVI, XVIa from Reaction Scheme 1), andthen oxidizing the separated stereoisomer to the indole (XVII andXVIIa). Further reactions can then be carried out if needed to obtain adesired optically active product of formula IV. The resolution procedurecan employ optically-active acids such as, for example, L-(+)-R-tartaricacid, (-)-dibenzoyltartaric acid, (+)-camphoric acid,(+)-10-camphorsulfonic acid, (-)-mandelic acid, (-)-malic acid,N-acetyl-L-glutamic acid, t-BOC-D-phenylglycine, D-(-)-S-tartaric acid,L-p-toluoyl-tartaric acid and the like.

Compounds illustrative of the scope of this invention include:

(±)-4-diallylamino-6-ethoxy-1,3,4,5-tetrahydrobenz[c,d]indole sulfate

(±)-4-methylethylamino-6-hydroxy-1,3,4,5-tetrahydrobenz[c,d]indoletartrate

(+)-4-dimethylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole maleate

(±)-4-diallylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole succinate

(±)-4-diethylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole phosphate

(-)-4-methyl-n-propylamino-6-n-propoxy-1,3,4,5-tetrahydrobenz[c,d]indoledihydrogenphosphate

(±)-4(di-n-proply)amino-6-acetoxy-1,3,4,5

tetrahydrobenz[c,d]indole bisulfate

(±)-4-dimethylamino-6-propionoxy-1,3,4,5-tetrahydrobenz[c,d]indolehydrobromide

(±)-4-diethylamino-6-benzyloxy-1,3,4,5tetrahydrobenz[c,d]indole tosylate

(-)-4-diallylamino-6-hydroxy-1,3,4,5-tetrahydrobenz[c,d]indole malate

(±)-4-(di-n-propyl)amino-6-hydroxy-1,3,4,5tetrahydrobenz[c,d]indolebenzoate

(-)-4-diethylamino-6-benzyloxy-1,3,4,5-tetrahydrobenz[c,d]indolephenylacetate

(+)-4-dimethylamino-6-mesyloxy-1,3,4,5-tetrahydrobenz[c,d]indole1,4-butyndioate

(±)-4-diallylamino-6-p-tosyloxy-1,3,4,5-tetrac,d]indole hydrochloride

(±)-4-dimethylamino-6-p-toluyl-1,3,4,5-tetrahydrobenz[c,d]indole sulfate

(+)-4-(di-n-propyl)amino-6-hydroxy-1,3,4,5tetrahydrobenz[c,d]indolefumarate

(-)-4-amino-6-hydroxy-1,3,4,5-tetrahydrobenz[c,d]indole propiolate andthe like.

Compounds according to IV above wherein X is O-C₁₋₃ alkyl are preparedaccording to the following reaction scheme. ##STR5## wherein R⁴ is H,CH₃ or C₂ H₅, X is O-C₁₋₃ alkyl or O-benzyl and R¹ and R² have theirprevious meanings.

According to Reaction Scheme 1, where X is methoxy, R⁴ is ethyl and R¹and R² are n-propyl for the sake of convenience only, a benzyl3-(5-methoxy-3-indolyl)propionate or the like ester (V) is reduced with(1) sodium cyanoborohydride to the corresponding 2,3-dihydro compound.(The Arabic numerals in Reaction Scheme 1 in parentheses refer toreagents used). With the saturation of the 2,3 double bond, the 1-aminogroup loses much of its acidic character and becomes sufficiently basicto enable it to be protected with a standard amine protecting group suchas an acyl group; i.e., as a benzoyl derivative. This protective groupis formed by reacting the 2,3-dihydro compound with (2) an acyl halideor anhydride; for example, benzoyl chloride in the presence of pyridine,to yield VI. The free acid (VII) is then prepared from the benzoyl ester(VI) by hydrogenation (3) over a noble metal catalyst in a mutual inertsolvent. The noble metal catalyst of choice is palladium-on-carbon. Thefree acid thus produced--3-(5-methoxy-1-benzoyl-2,3-dihydro-3-indolyl)-propionic acid--iscyclized with a dehydrating agent, preferably polyphosphoric acid (PPA)(4). This reagent is a particularly convenient cyclizing agent since itcan also serve as a solvent for the cyclization reaction. Alternatively,the acid chloride can be prepared and cyclized in the presence of aLewis acid, preferably AlCl₃ --see Kornfeld et al., J.A.C.S., 78, 3087(1956) to yield the desired benz[c,d]indole. The cyclized product (VIII)is 1-benzoyl-5-oxo-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole.Reduction (5) of the oxo group with sodium borohydride in a loweralkanol such as ethanol yields the corresponding 5-oxy derivative (IX).This hydroxy derivative can be dehydrated by heating in the presence ofan acidic catalyst (p-toluene sulfonic acid (6) for example) in an inertsolvent to yield 1-benzoyl-6-methoxy-1,2,2a,3-tetrahydrobenz[c,d]indole(X). I prefer, however, to use an acidic ion exchange resin as the acidcatalyst. The 4,5 double bond is then epoxidized with a reagent such asm-chloroperbenzoic acid (7) in an inert solvent to yield a 4,5-epoxyderivative (XI). Rearrangement of the epoxide by heating in the presenceof zinc iodide (8) yields an isomeric ketone, (isomeric with VIII),1-benzoyl-4-oxo-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole (XII).

Next, the hydroxylamine derivative of this isomeric ketone (XIII) isformed (9) and the resulting oxime reduced with Raney nickel (10) toyield a mixture of amino derivatives, trans-dl andcis-dl-1-benzoyl-4-amino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole(XIV and XIVa). Alkylation (11) of the primary amine group by standardprocedures, for example reductive alkylation with an aldehyde, R⁴ CHO,and sodium cyanoborohydride in acetonitrile, to which an equivalent ofglacial acetic acid has been added, yields the symmetricaldi-alkylamine; (XV and XVa). Treatment of the mixture of these cis-dland trans-dl tertiary amines with aqueous acid (12) yields a mixturecomprisingtrans-dl-4-dialkylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indoleand the corresponding cis-dl compound. Oxidation of this mixture with,for example, N-chloro succinimide (13) in the presence of dimethylsulfide and triethylamine (14), yields(±)-4-dialkylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole (XVII andXVIIa represent the two enantiomers). The racemic mixture can readily beconverted to the salt form (XVIII and XVIIIa) by standard procedures(15).

While the above procedure has been illustrated with reference to thepreparation of a 6-methoxy derivative, the procedure is equallyapplicable to the preparation of other 6-C₁₋₃ alkyloxy compounds or of6-benzyloxy compounds or the 6-fluoro compound.

The procedure represented in Reaction Scheme 1 is particularly usefulfor preparing compounds according to IV in which the 6-derivative (Xgroup) is alkyloxy These 6-alkyloxy compounds can be prepared by analternate procedure. According to this procedure, the intermediatedisclosed by Bach and Kornfeld in U.S. Pat. No. 4,110,339, Example 1; towit,1-benzoyl-4-(di-n-propyl)amino-1,2,2a,3,4,5-hexahydrobenz[c,d]indole orthe corresponding 4-dimethylamino, 4-diethylamino or mixed N,N-dialkylderivative, is brominated by standard procedures at C-6. The 6-bromocompound thus formed, can be treated with sodium methoxide in thepresence of CuI to yield a 6-methoxy derivative. The benzoyl protectinggroup is then removed from the indole nitrogen by treatment with aqueousacid. As in the procedure in Reaction Scheme 1, as a final step, the6-alkoxysubstituted-4-dialkylamino-1,2,2a,3,4,5-hexahydrobenz[c,d]indole isoxidized to reconstitute the indole ring and yield a compound accordingto IV above wherein X is alkyloxy. The 6-benzyloxy derivatives areprepared in similar fashion.

I have developed a process for preparing(±)-4-dialkylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole whichcommences with brominating the Bach-Kornfeld (loc.cit.) cyclic ketone.This process is set forth in Reaction Scheme 2 below, using thepreparation of a 4-di-n-propyl derivative for illustrative purposesonly. ##STR6##

Specifically, 1-benzoyl-5-oxo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole (XX)(from Kornfeld et al, J.A.C.S., 78, 3887 (1956) compound 4) ishydrolysed in acid to 5-oxo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole (XXI)(compound 10 of Kornfeld et al when R is H). The 5-ketone is reduced toa 5-hydroxyl[(±)-5-hydroxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole (XXII)]with an alkali metal borohydride or alumina hydride in a mutual inertsolvent. Bromination in acetic acid yields the (±)-6-bromo-5-hydroxyderivative (XXIII). This compound is then reacted with 2 moles of ethylchloroformate to yield a(±)-1-ethoxycarbonyl-5-ethoxycarbonyloxy-6-bromo1,2,2a,3,4,5-hexahydrobenz[c,d]indole(XXIV). This double acylation is conveniently carried out in pyridinesolution (though other inert solvents may be used) containing theoptional catalyst DMAP. Heating the 5-ethoxy carbonyloxy compoundresults in elimination to produce1-ethoxycarbonyl-6-bromo-1,2,2a,3-tetrahydrobenz[c,d]indole (XXV).Epoxidation of the thus-produced double bond using, conveniently,m-chloroperbenzoic acid or other peracid as in Reaction Scheme 1 withthe corresponding 1-benzoyl derivative (X→XI). Rearrangement of theepoxide on heating with ZnI₂ yields the 4-oxo derivative (XXVII). Hereagain, the reaction conditions from Reaction Scheme 1 (XI XII) can beemployed. Reductive amination with n-propyl bromide and NaCNBH₃ or othersuitable reducing agent, yields(±)-1-ethoxycarbonyl-4-n-propylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole(XVIII). This secondary amine can then be acylated with propionicanhydride and the N-propionyl group reduced with BH₃ in TFA or NaCNBH₃or other suitable reducing agent to yield the 4-di-n-propyl compound,(±)-1-ethoxycarbonyl-4-di-n-propylamino6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole (XXXI). Alternative, thesecondary amine XXVIII can be acylated as with n-propyliodide in thepresence of an organic base to yield XXXI directly. Finally, hydrolysisof the 1-ethoxycarbonyl amide yields XXXI, oxidation of which with MnO₂or with N-chlorosuccinimide in the presence of dimethyl sulfide yields a2,2a-didehydro derivative (XXXII). An inert solvent is employed. Ingeneral, the reaction conditions from Reaction Scheme 1 are operativehere. (XVI+XVIa to XVII+XVIIa). The ultimate product of this reaction(XXXII) is the desired intermediate(±)-4-di-n-propylamino-6-bromo-1,3,4,5-tetrahydrobenz[c,d]indole.

The above reaction sequence has been illustrated with respect to thepreparation of a 4-di-n-propyl derivative. It will be apparent to thoseskilled in the art that substitution of methyl, ethyl or allyl amine forn-propylamine in the preparation of XXVIII would yield a 4-methyl, ethylor allyl amino group Likewise the thus formed secondary amine can beacylated (XXVIII where the amine group is n-propyl but could be Me, Etor allyl) with formic, acetic, acrylic or propionic acid and theresulting N-acyl group reduced to an alkyl or allyl group to form acompound of the formula ##STR7## wherein X is O-C₁₋₃ alkyl, and R⁵ andR⁶ are, individually, methyl, ethyl, n-propyl or allyl. It will be notedthat the above procedure provides an easy route to unsymmetricallysubstituted C-4 tertiary amines.

Alternatively, the secondary amine (XXVIII where the amine group isn-propyl but could be methyl, ethyl or allyl) can be directly alkylatedwith CH₃ I, C₂ H₅ I, n-propyl iodide or allyl bromide to yield the sametertiary amine (XXXa).

Compounds according to IV in which X is hydroxy are prepared bydebenzylation of the corresponding derivative in which X is benzyloxy.Alternatively, the 6-bromo group in a (±)-4-dialkyl (orallyl)amino-6-bromo-1,3,4,5-tetrahydrobenz[c,d]indole, can be replacedby a benzyloxy group. Debenzylation by hydrogenation in neutral orslightly acidic solution is a convenient way to prepare the 6-hydroxyderivative, although the yield is poor. The 6-hydroxy derivatives arerelatively unstable, and it is prudent to protect a compound containingthis group from oxidation by acylation, as with acetic anhydride, or byimmediate conversion to a salt. The 6-acyloxy derivatives thus formedcan act as prodrugs in that, after administration, the acyloxy groupwill be hydrolyzed to yield the free 6-hydroxy compound in vivo.

Compounds according to IV above have a single asymmetric center at C-4and occur commonly as a racemate. However, as has been pointed out inthe above discussion of Reaction Scheme 1, compounds according to VIIIthrough XVI and XVIa have an additional asymmetric center at C-2a, whichcenter is removed by the oxidative procedures (13) and (14). Thus,compounds IX, XIV, XIVa, XV, XVa, XVI and XVIa each have two asymmetriccenters (at C-2a and C-4) and exist as two racemic pairs convenientlydesignated as the trans-dl and the cis-dl racemates.

This invention is further illustrated by the following specificexamples.

EXAMPLE 1 Preparation of(±)-4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole

A solution was prepared by dissolving 26 g. of benzyl2-(5-methoxy-3-indolyl)propionate in 500 ml. of glacial acetic acid. Thesolution was cooled and stirred. Twenty-six grams of sodiumcyanoborohydride were added. The resulting reaction mixture was stirredat ambient temperature for about 3.5 hours at which time TLC showed nopeak corresponding to starting material, indicating the reaction hadgone substantially to completion. The reaction mixture was then pouredinto 2 1. of water and the aqueous mixture extracted with severalportions of methylene dichloride. The methylene dichloride extracts werecombined, the combined extracts washed with dilute aqueous sodiumbicarbonate and then dried. Removal of the solvent in vacuo yielded 25.5g. of a viscous oil comprising benzyl 2-(5-methoxy-3indolinyl)propionateformed in the above reaction. The oil was dissolved in chloroform and 8ml. of pyridine were added to the chloroform solution. Next, 13.9 g. ofbenzoylchloride were added while the solution was being cooled in anice-water bath. After the addition had been completed, the acylationmixture was stirred for about one hour and was then washed once withwater, twice with 1N aqueous hydrochloric acid, twice with diluteaqueous sodium bicarbonate and finally with saturated aqueous sodiumchloride. The aqueous washes were all discarded. The organic layer wasdried and the solvent removed in vacuo. The resulting residue wasdissolved in ethyl acetate and the ethyl acetate solution passed over ashort Florisil column. Ethyl acetate was removed from the eluate. Benzyl2-(1-benzoyl-5-methoxy-3-indolinyl)propionate thus prepared crystallizedon standing overnight. The crystals were washed with cyclohexane.Recrystallization from a toluene-hexane solvent mixture yielded 30.2 g.of benzyl 2-(1-benzoyl-5-methoxy-3-indolinyl)propionate melting at about102-3° C.

The compound had the following physical properties:

Ultraviolet spectrum; λ_(max) (MeOH) 274 nm (e=11,900); NMR(CDCl₁₃)δ=2.0 (mult, 2H, α-CH2), 2.4 (mult, 2H, β-CH₂), 3.3 (mult, 1H,3-H), 3.7 (mult, 1H, 2β-H), 3.8 (s, 3H, OCH₃), 4.2 (qt, 1H, 2α-H), 5.1(s, 2H, PhCH₂), 6.7 (mult, 1H, 7-H), 6.9 (brs, lH, 4-H), 7.3 (mult, 1H,8-H), 7.4 (s, 5H, Ph), 7.5 (s, 5H, Ph-CO).

Analysis Calculated: C, 75.16; H, 6.07; N, 3.37.

Found: C, 74.96; H, 5.88; N, 3.19.

Thirty grams of benzyl 2-(1-benzoyl-5-methoxy-3-indolinyl)propionatewere hydrogenated over palladium-on-carbon in ethanol to remove thebenzyl ester group. 2-(1-Benzoyl-5-methoxy-3-indolinyl)propionic acidthus formed crystallized on cooling in the hydrogenation bomb andseparated with the catalyst on filtration. The desired product wasdissolved away from the catalyst by washing with hot ethanol. Ethanolwas removed from the combined filtrate and washings by evaporation. Theresulting residue was dissolved in tetrahydrofuran (THF). The THFsolution was filtered and the THF removed from the filtrate in vacuo.The resulting residue was crystallized from about 500 ml. of ethanol;yield= 21.2 g. of 2-(1-benzoyl-5-methoxy-3-indolinyl)propionic acidmelting at 169-70° C.

Ultraviolet spectrum: δ_(max) (MeOH) 274 nm (ε=12,200)

Analysis Calculated: C, 70.14; H, 5.89; N, 4.31.

Found: C, 70.42; H, 5.99; N, 4.62.

A repeat hydrogenation on 17 g. of ester starting material in 125 ml. ofTHF and 125 ml. of ethanol using 0.5 g. of 10% Pd/C and a hydrogenpressure of 2.74× 10⁶ dynes/cm² gave a 94% yield of the desired acid.

Five grams of 2-(1-benzoyl-5-methoxy-3-indolinyl)propionic acid werecyclized in 100 g. of polyphosphoric acid (PPA) at 80° C. TLC after onehour of reaction time indicated little or no starting material present.The reaction mixture was therefore poured over ice. The resultingaqueous mixture was extracted several times with methylene dichloride.The methylene dichloride extracts were combined and the combinedextracts washed with sodium bicarbonate until the washings remainedbasic to litmus. The extracts were then concentrated in vacuo and theresulting residue recrystallized from a toluene/hexane solvent mixtureto yield crystalline1-benzoyl-5-oxo-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole formedin the above cyclization. Recrystallization yielded about 4.5 g. ofcompound melting at about 147.5-149° C.

The compound had the following physical characteristics:

Infrared spectrum (KBr): 1634, 1672 cm⁻¹

NMR (DMSO-d₆)δ=1.81 (quintet, 1H, 3δ-H), 2.18 (brd, 1H, 3α-H), 2.53(mult, 2H, 4-CH₂), 3.33 (mult, 1H, 2β-H), 3.61 (mult, 1H, 2a-H), 3.80(s, 3H, OCH₃), 4.14 (mult, 1H, 2α-H), 6.97 (mult, 1H, 7-H), 7.59 (mult,5H, Ph), 8.11 (mult, 1H, 8-H).

Analysis Calculated: C, 74.25; H, 5.58; N, 4.56.

Found: C, 73.99; H, 5.84; N, 4.37.

A second large-scale run using 18.95 g. of free acid starting materialgave a crude product which, when combined with the product from thefirst reaction, yielded, after recrystallization, 29.9 g. (84% yield) ofcyclized product melting at about 152-3° C.

A suspension of 4.2 g. of1-benzoyl-5-oxo-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole in 50ml. of ethanol was prepared. A solution of 0.77 g. of sodium borohydridein 25 ml. of ethanol was added thereto in dropwise fashion withstirring. The suspended ketone slowly dissolved to produce a greenishsolution. After about four hours of stirring at room temperature, thenow homogeneous reaction mixture was concentrated in vacuo. Fifty ml. ofwater were added to the residue and the resulting basic aqueous solutionneutralized with 3N aqueous hydrochloric acid to pH =7. This neutralaqueous layer was extracted several times with methylene dichloride. Themethylene dichloride extracts were combined and the combined extractswashed with saturated aqueous sodium chloride and then dried. Removal ofthe solvent by evaporation left a viscous oil. Chromatography of thisoil over silica gel using ethyl acetate as the eluant yielded 3.83 g.(90% yield) of(±)-1-benzoyl-5-hydroxy-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole.Recrystallization from ethyl acetate of a 100 mg. sample of thecrystalline product gave 68 mg. of the mixture of epimeric alcohols.

Infrared spectrum (CHCl₃) 1632 cm⁻¹ ;

Ultraviolet spectrum: δ_(max) (MeOH) 273 nm (ε=7900), 302 nm (sh)(ε=6000)

Analysis Calculated: C, 73.77; H, 6.19; N, 4.53.

Found: C, 73.71; H, 6.03; N, 4.43.

A reaction mixture was prepared from 3.7 g. of(±)-1-benzoyl-5-hydroxy-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole,1 g. of a macroreticular dehydration catalyst (AMBERLYST-15 resin) and50 ml. of toluene. The reaction mixture was heated to reflux for aboutone hour in an apparatus equipped with a Dean-Stark trap. The amount ofwater collected in the trap plus TLC on the reaction mixture indicatedthat dehydration was complete at this time.(±)-1-Benzoyl-6-methoxy-1,2,2a,3-tetrahydrobenz[c,d]indole was formed inthe above dehydration. The reaction mixture was filtered through filtercell. Evaporation of the filtrate to dryness yielded a viscous oil,which crystallized on trituation with hexane to give 3.34 g. of(±)-1-benzoyl-6-methoxy-1,2,2a,3-tetrahydrobenz[c,d]indole (96% yield).Recrystallization of a 100 mg. sample from a toluene/hexane solventmixture yielded 85 mg. of compound melting at about 125.5-127° C.

Ultraviolet spectrum: δ_(max) (MeOH) 271 nm (ε=13,300), 320 nm (sh)(ε=3500).

Analysis Calculated: C, 78.33; H, 5.88; N, 4.81.

Found: C, 78.09; H, 5.68; N, 4.65.

A solution of 3.2 g. of (±)-1-benzoyl-6

methoxy-1,2,2a,3-tetrahydrobenz[c,d]indole in 120 ml. of chloroform wascooled to about 0° C. with stirring. Three and sixty-one hundredthsgrams of 80-85% m-chloroperbenzoic acid were added thereto. Theresulting solution was stirred in the 0-5° C. range for about five hoursafter which time TLC showed no remaining starting material. The reactionmixture was then washed twice with cold 1N aqueous sodium hydroxide,twice with dilute aqueous sodium bisulfite and again with 1N aqueoussodium hydroxide. The washings were discarded. The remaining organiclayer was then dried and the solvent removed in vacuo. The residual oilcrystallized to yield1-benzoyl-4,5-epoxy-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole. Thecompound melted at 174-175° C. after recrystallization from toluene.

Ultraviolet spectrum: δ_(max) (MeOH) 273 nm (ε=10,700), 300 nm (sh)(ε=7700).

Analysis Calculated: C, 74.25; H, 5.58; N, 4.51.

Found: C, 73.98; H, 5.70; N, 4.37.

A solution benzene solution was, without further purification, added toa suspension of 1.8 g. of zinc iodide in 150 ml. of benzene. (Thesuspension was dried by distillation of about 30 ml. of benzenecontaining some benzene-water azeotrope.) The addition was made indropwise fashion over a ten minute period at a temperature of about 50°C. The reaction mixture was heated to refluxing temperature for about 50minutes and was then cooled. The cooled reaction mixture was washed withdilute aqueous hydrochloric acid in order to decompose any reactioncomplex present. The organic solution was next washed with saturatedaqueous sodium bicarbonate. The solvent was removed from the organiclayer in vacuo and the resulting residue was recrystallized from ethylacetate.(±)-1-Benzoyl-4-oxo-6-methoxy-1,2,2a,3,-4,5-hexahydrobenz[c,d]indolethus prepared melted at about 188-189° C. after two recrystallizations(yield=72%).

The compound had the following physical characteristics:

Infrared spectrum (CHCl₃): 1636, 1717 cm-¹ ; NMR (CDCl₃):δ=2.34 (qt, 1H,3β-H), 2.90 (brd, 1H, 3α-H), 3.31 (d, 1H, 5β-H), 3.66 (d, 1H, 5α-H), 3.8(mult, 2H, 2a-H and 2β-H), 3.80 (s, 3H, OCH₃), 4.33 (mult, 1H, 2α-H),6.75 (mult, 1H, 7-H), 7.54 (mult, 5H, Ph), 7.96 (mult, 1H, 8-H).

Analysis Calculated: C, 74.23; H, 5.58; N, 4.56.

Found: C, 74.24; H, 5.37; N, 4.50.

A reaction mixture was prepared from 207 mg. of(±)-1-benzoyl-4-oxo-6-methoxy-1,2,2,3,4,5-hexahydrobenz-[c,d]indole and200 mg. of hydroxylamine hydrochloride in 5 ml. of ethanol plus 1 ml. ofpyridine. The reaction mixture was heated to reflux temperature forabout 15 minutes and then was cooled. An equal volume of water wasadded. At this point, the oxime formed in the above reaction began tocrystallize. Crystallization was allowed to proceed to completion. Thereaction mixture was filtered. Additional water added to the filtrateproduced a second crop of crystals; total yield =0.21 g. (98% totalyield). The crystalline product, a mixture of syn andanti-(±)-1-benzoyl-4-oximino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indoleformed in the above reaction, melted at about 189-190° C.Recrystallization yielded material melting at about 193° C.

Mass spectrum: 322 (mass peak).

Analysis Calculated: C, 70.79; H, 5.63; N, 8.69.

Found: C, 70.86; N, 5.47; N, 8.46.

A mixture of syn and anti-oximes (2.46 g.) was hydrogenated over Raneynickel in ethanolic axmmonia at about 100° C. for about 10 hours. Thehydrogenation solution was filtered to remove the catalyst. The filtratewas evaporated to dryness leaving a viscous oil comprising(±)-1-benzoyl-4-amino-6-methoxy-1,2,2a, 3,4,5-hexahydrobenz[c,d]indoleformed in the above hydrogenation. The product was a mixture of tworacemates named as the cis-(±) and trans-(±)-racemate for convenience.(Optical centers are at C-2a and C-4.) The viscous oil was dissolved in25 ml. of 1N aqueous hydrochloric acid and the acidic solution washedseveral times with methylene dichloride. These washings were discarded.The aqueous solution was then made basic (pH =about 12) with aqueoussodium hydroxide and then extracted with chloroform. The chloroformlayer was filtered to remove an insoluble material. The chloroform wasremoved from the filtrate in vacuo. Recrystallization of the resultingresidue from a mixture of toluene and hexane yielded 1.48 g. of crystalsmelting at 140-144° C. An additional 0.63 g. of a pale yellow glass wasobtained from the filtrate; total yield=2.11 g. (90%). It was determinedthat the crystalline material was one racemic mixture in which the aminegroup and the ring junction hydrogen were on opposite sides of thehexahydrobenz[c,d]indole ring system, designated as the trans-(±)racemate, and the yellow oil represented a racemic mixture in which theamine group and the 2a-hydrogen were on the same side of thebenz[c,d]indole ring system, designated as thecis-amino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole, had thefollowing elemental analysis:

Analysis Calculated: C, 74.00; H, 6.54; N, 9.08.

Found: C, 74.21; H, 6.57; N, 8.81.

Ultraviolet spectrum: λ_(max) (MeOH) 275 nm (ε=11,500), 300 nm (sh)(ε=9000);

Mass spectrum: 308 (mass peak)

A reaction mixture was prepared from 0.55 g. of the cis-racemate, 0.75ml. of propionaldehyde and 5 ml. of acetonitrile. Eighteen hundredthsgrams of sodium cyanoborohydride were added thereto. The pH of thereaction mixture was adjusted to about 7 with a few drops of glacialacetic acid, at which point a vigorous reaction ensued. The reactionmixture was stirred under a nitrogen atmosphere for about three hourswith the occasional addition of a drop of glacial acetic acid. At thispoint in time, TLC indicated there was no longer any peak correspondingto starting material and only one major spot. The solvent was removedfrom the reaction mixture and the residue treated with 5N aqueous sodiumhydroxide. The alkaline layer was extracted with methylene dichloride.The methylene dichloride extracts were combined and the combinedextracts dried. Removal of the solvent left a viscous pale yellow oil asa residue. Chromatography of this residual oil over silica gel in anHPLC preparative column using a 1:1 ethyl acetate/toluene solventmixture as the eluant 25 produced fractions containingcis-(±)-1-benzoyl-4-di-n-propylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole relatively free of contaminatingmaterials according to TLC. Elemental analysis indicated, however, thatthe product was slightly impure (weight=0.56 g.).

In a later run at twice the scale, the free base obtained in ethersolution, as above, was converted to the hydrochloride salt using aslight excess of 2.4 M ethereal HCl; yield=63%. The hydrochloride salthad the following elemental analysis.

Analysis Calculated: C, 69.99; H, 7.75; N, 6.53; Cl, 8.26.

Found: C, 69.92; H, 7.67; N, 6.47; Cl, 8.03.

Ultraviolet spectrum: λ_(max) (MeOH) 274 nm (ε=10,500), 300 nm (sh)(ε=7200);

Mass spectrum: 392 (mass peak)

Following the above procedure, 2.41 g. ofcis-(±)-1-benzoyl-4-amino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indolein 25 ml. of acetonitrile was reacted with 5.2 ml. of 37% formalin and0.78 g. of NaBH₃ CN at pH=7. The reaction mixture 2N aqueous sodiumhydroxide and the alkaline mixture extracted with ether. The etherealextract was in turn extracted with 1N aqueous hydrochloric acid. Theacidic solution was then made basic with 2N aqueous sodium hydroxide and1-benzoyl-6-methoxy-4-dimethylaminohexahydrobenz[c,d]indole formed inthe above reaction, being insoluble in alkali, separated and wasextracted into methylene dichloride. Removal of the methylene dichlorideyielded a residue which was purified by chromatography over silica gelusing ethyl acetate as the eluant. Fractions containing the desiredamine base were combined. An excess of 3.2 M ethereal hydrogen chloridewas added to the combined fractions and the solvent removed byevaporation to leave 1.99 g. ofcis-(±)-1-benzoyl-4-dimethylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole hydrochloride. The salt had the followingphysical characteristics:

Ultraviolet spectrum: λ_(max) (EtOH) 274 nm (ε=12,200), 300 nm (sh)(ε=9300);

Mass spectrum: 335 (M-1 peak).

Analysis calculated: C, 67.64; H, 6.76; N, 7.51.

Found: C, 67.77; H, 6.87; N, 7.51.

The above procedure was repeated with the crystalline fractioncomprising trans-(±)-1-benzoyl-4-amino-6-methoxy1,2,2a,3,4,5-hexahydrobenz[c,d]indole. One and sixty-three hundredthsgrams of this racemate were dissolved in 12.5 ml. of acetonitrile and1.85 ml. of propionaldehyde were added. Forty-five hundredths grams ofsodium cyanoborohydride were then added followed by the dropwiseaddition of sufficient acetic acid to bring the pH to about 7. Thereaction mixture was stirred for about three hours while occasionallyadding a drop of glacial acetic acid. At the end of this time, TLCindicated absence of starting material. The reaction mixture wastherefore poured into 2N aqueous sodium hydroxide solution and thealkaline mixture extracted with ether. The ether extracts were combinedand the combined extracts washed with water. The ether solution was thencontacted with 1N aqueous hydrochloric acid thereby extractingtrans-(±)-1-benzoyl-4-(di-n-propyl)amino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indoleformed in the above reaction. The acidic aqueous layer was extractedwith ether and the ether extract discarded. The acidic aqueous layer wasthen made basic with sodium hydroxide and the free base extracted intomethylene dichloride. Methylene dichloride was removed by evaporationand the free base remaining was dissolved in dilute aqueous hydrochloricacid containing some methanol. The procedure of taking the free baseinto acidic solution, extracting the acidic solution with ether, makingthe acidic solution alkaline and reextracting the free base intomethylene dichloride was repeated. Evaporation of ethylene dichloridefrom the final base extract yielded a viscous oil weighing 1.07 g. (63%yield). TLC indicated essentially single spot material. The compound wasconverted to the hydrochloride salt by standard procedures.Trans-(±)-1-benzoyl-4-di-n-propylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indolehydrochloride thus prepared had the following analysis.

Analysis Calculated: C, 69.99; H, 7.75; N, 6.53; Cl, 8.26.

Found: C, 69.92; H, 7.52; N, 6.26; Cl, 8.02.

Ultraviolet spectrum λ_(max) (MeOH) 274 nm (ε=10,800), 300 nm (sh)(ε=8400);

Mass spectrum: 392 (mass peak)

Trans-(±)-1-benzoyl-4-dimethylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indolecan be prepared in similar fashion by reductive alkylation of the6-amino derivative with HCHO and NaBH₃ CN.

Cis-(±)-1-benzoyl-4-di-n-propylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole(0.507 g.) and 5 ml. of 6N aqueous hydrochloric acid were refluxed undera nitrogen atmosphere for three hours. TLC at the end of this timeindicated that hydrolysis of the benzamide group was complete. Theaqueous solution was therefore diluted with water. Benzoic acid formedin the hydrolysis crystallized on cooling and was separated byfiltration. The acidic aqueous layer was extracted twice with equalvolumes of ether to remove the last traces of benzoic acid. The etherextracts were discarded. The acidic aqueous layer was then made basic byaddition of 5N aqueous sodium hydroxide. The alkaline layer wasextracted several times with methylene dichloride. The methylenedichloride extracts were combined and dried. Evaporation of themethylene dichloride yielded an oil that was purified by passage over ashort silica gel column using ethyl acetate as the eluant. The purifiedproduct was crystallized from isooctane.Cis-(±)-4-di-n-propylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indolethus prepared melted at 75-78° C. The compound had the followingphysical characteristics.

Ultraviolet spectrum: λ_(max) (EtOH) 237 nm (ε=7400), 299 nm (ε=3000);

NMR (CDCl₃) δ=0.87 (t, 6H, C-CH₃), 1.45 (mult, 5H, CH₂ Me and 3β-H),2.20 (sextet, 1H, 3α-H), 2.49 (mult, 5H, CH₂ Et and 5β-H), 2.91 (qt, 1H,5α-H), 3.12 (mult, 2H, 2β-H and 4-H), 3.26 (mult, 1H, 2a-H), 3.64 (t,1H, 2α-H), 3.77 (s, 3H, OCH₃), 6.48 (qt, 2H, 7-H and 8-H).

Analysis Calculated: C, 74.96; H, 9.79; N, 9.71.

Found: C, 75.24; H, 9.55; N, 9.60.

Following the above procedure, 1.90 g. ofcis-(±)-1-benzoyl-4-dimethylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indolewas debenzoylated by treatment of the hydrochloride salt with acid (20ml. of 3 M aqueous sulfuric acid). After cooling, the reaction mixturewas extracted twice with ether to remove benzoic acid formed as aby-product in the above reaction. The reaction mixture was then madebasic with 5 M aqueous sodium hydroxide.Cis-(±)-4-dimethylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indoleformed in the above reaction separated and was extracted into methylenedichloride. Removal of the solvent from the extract left a dark oilwhich was purified by chromatography over silica gel using 1:19methanol-ethyl acetate solvent mixture as the eluant. Removal of thesolvent from fractions containing the desired compound yielded 1.06 g.ofcis-(±)-4-dimethylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indolehaving the following elemental analysis.

Analysis Calculated: C, 72.38; H, 8.68; N, 12.06.

Found: C, 72.18; H, 8.72; N, 11.83.

The compound had the following physical characteristics:

Infrared spectrum: λ_(max) (EtOH) 239 nm (ε=7400), 300 nm (ε=3100);

Mass spectrum: 232 (mass peak)

Trans-(±)-1-benzoyl-4-(di-n-propyl)amino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indolewas hydrolyzed in similar fashion to yield (79%)trans-(±)-4-(di-n-propyl)amino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indolemelting at 71-3° C. after recrystallization from isooctane.

The compound had the following physical characteristics:

Infrared spectrum: λ_(max) (EtOH) 239 nm (ε=7100), 299 nm (ε=3100);

NMR (CDCl₃) δ=0.89 (t, 6H, C-CH₃), 1.41 (quintet, 1H, 3β-H), 1.48(sextet, 4H, CH₂ Me), 2.16 (brd, 1H, 3α-H), 2.47 (mult, 5H, CH₂ Et and5β-H), 2.83 (qt, 1H, 5α-H), 3.14 (mult, 3H, 2a-H and 2β-H and 4-H), 3.48(brs, 1H, N-H), 3.62 (t, 1H, 2a-H), 3.77 (s, 3H, OCH3), 6.46 (qt, H, 7-Hand 8-H).

Analysis Calculated: C, 74.96; H, 9.79; N, 9.71.

Found: C, 74.72; H, 9.57; N, 9.54.

Cis-(±)-4-di-n-propylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indolewas oxidized to the tetrahydrobenz[c,d]indole by the followingprocedure. Three hundred twenty-one thousandths grams of the indolinefree base and 0.12 ml. of dimethylsulfide were dissolved in 5 ml. ofmethylene dichloride. The solution was cooled to about -70° C. in a dryice-acetone bath. A solution of 0.175 ml. of t-butylhypochlorite in 3ml. of methylene chloride was added to the reaction mixture over a 30minute period. After the addition had been completed, the reactionmixture was stirred for two hours at dry ice-acetone temperatures. Nexta solution of 0.13 g. of sodium and 3 ml. of ethanol was added, also indropwise fashion. The resulting mixture was allowed to warm to roomtemperature and was stirred at that temperature for about one hour, atwhich time it was washed twice with water and the water wash discarded.The solvent was removed from the organic layer to leave a dark brownresidue which was chromatographed over silica gel. The chromatographiccolumn was prepared in a solvent mixture comprising 10% triethylamine,10% ethyl acetate and 80% toluene. The desired product was eluted with a1:9 ethyl acetate/toluene solvent mixture. Chromatographic fractionscontaining this product were combined and the solvent removed therefromin vacuo leaving a colored residual free base consisting of(±)-4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indoleformed in the above oxidation. The residual oil was converted to thehydrochloride salt which decomposed at about 110° C. The salt had thefollowing analysis:

Analysis Calculated: C,66.96; H, 8.43; N, 8.68; Cl, 10.98.

Found: C, 66.84; H, 8 58; N, 8.44; Cl, 10.76.

NMR (CDCl₃) δ=1.02 (mult, 6H, 2-CH₃), 1.99 (mult, 4H, CH₂ Me), 2.94(mult, 1H, 5β-H), 3.04 (qt, 1H, 5α-H), 3.17 (mult, 5H, CH₂ Et and 3α-H),3.47 (mult, 1H, 3β-H), 3.80 (t, 1H, 4-H), 3.89 (s, 3H, OCH₃), 6.85 (d,1H, 8-H), 6.94 (s, 1H, 2-H), 7.19 (d, 1H, 7-H), 8.18 (s, 1H, N-H), 12.14(brs, 1H, HCl);

Mass spectrum: 286 (mass peak)

The trans-(±)-racemate was oxidized slightly different fashion asfollows. A solution of 0.35 g. of 98% N-chlorosuccinimide in 10 ml. ofdistilled methylene dichloride was cooled to about 0° C. while 0.3 ml.of methylsulfide were added in dropwise fashion under a nitrogenatmosphere. After stirring at ice bath temperature for 15 minutes, thesolution was cooled to dry ice-acetone temperature (-70° C.). Next, asolution of 0.72 g. oftrans-(±)-4-di-n-propylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indolein 2 ml. of methylene dichloride was added in a dropwise fashion over a30 minute period. The resulting reaction mixture was stirred for another30 minutes after which time 1 ml. of triethylamine was added in dropwisefashion. This new reaction mixture was stirred at dry ice-acetonetemperature for another 15 minutes and was then allowed to warm to roomtemperature. The reaction mixture was next washed three times with waterand the water extracts reextracted with ether. The methylene dichloridesolution and ether extracts were combined and the solvent removedtherefrom in vacuo leaving a viscous brown oil. Chromatography oversilica gel (as with the cis-racemate) gave 0.303 g. of(±)-4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indoleformed in the above reaction. Two hundred thirty-five hundredths gramsof free base were eventually obtained and converted to the hydrochloridesalt using ethereal hydrogen chloride (2.38 molar).

Following the above procedure, a solution of 0.78 g. ofN-chlorosuccinimide and 0.5 ml. of dimethylsulfide in 25 ml. of toluenewas used to oxidize 1.0 g. ofcis-(±)-4-dimethylamino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indoleat dry ice-acetone temperatures. One and twenty-five hundredths ml. oftriethylamine were added. The reaction mixture was worked up and thecrude residue, comprising(±)-4-dimethylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole formedin the above oxidation, was purified by chromatography over silica gel.Ethyl acetate containing increasing (0-5%) methanol was used as theeluant. Fractions containing the desired tetrahydrobenz[c,d]indole werecombined to yield 0.15 g. of the compound.

The free base in ethereal solution was converted to the hydrochloridesalt with 4.5 M ethereal HCl, which salt had the following elementalanalysis.

Analysis Calculated: C, 63.03; H, 7.18; N, 10.50; Cl, 13.29.

Found: C, 62.83; H, 7.10; N, 10.29; Cl, 13.14.

The compound had the following physical characteristics:

NMR (CDCl₃) δ=2.86 (d, 3H, NCH₃), 2.9 (mult, 1H, 5β-H), 2.97 (d, 3H,NCH₃), 3.04 (qt, 1H, 5α-H), 3.18 (qt, 1H, 3α-H), 3.51 (qt, 1H, 3β-H),3.71 (mult, 1H, 4-H), 3.90 (s, 3H, OCH3), 6.87 (d, 1H, 8-H), 6.96 (s,1H, 2-H), 7.19 (d, IH, 7-H), 8.00 (s, 1H, N-H), 12.79 (brs, H, HCl);

Mass spectrum: 230 (mass peak).

EXAMPLE 2 Alternative Preparation of(±)-4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole

A mixture containing 5.0 g. of5-oxo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole in 100 ml. of ethanol wastreated with 1.63 g. of sodium borohydride in portions. The resultingmixture was stirred for about four hours after which time the bulk ofthe ethanol was removed in vacuo. The resulting residue was taken up inwater, and the aqueous mixture acidified with 3M hydrochloric acid. Theaqueous solution was filtered, and the filtrate treated with diluteaqueous sodium hydroxide. (±)-5-Hydroxy-1,2,2a,3,4,5,-benz[c,d]indoleformed in the above reaction was insoluble in the basic medium andprecipitated. The precipitate was collected, washed with water and thendried. Four and seventy-two hundredths grams of(±)-5-hydroxy-1,2,2a,3,4,5-hexahydrobenz[ c,d]indole (93% yield) wereobtained. The material was one spot by TLC; m.p.=205° C.

Analysis Calculated: C, 75.83; H, 6.94; N, 8.04.

Found: C, 75.75; H, 7.16; N, 7.89.

A solution of 35 g. of(±)-5-hydroxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole in 900 ml. of coldglacial acetic acid was treated with 22 g. of bromine dissolved in 100ml. of glacial acetic acid. After the bromine color had been discharged,the acetic acid was removed in vacuo. The residue, comprising a mixtureof (±)-5-hydroxy-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole and thecorresponding 6,8-dibromo derivative was diluted with water and theaqueous mixture made basic with 5M aqueous sodium hydroxide. Thehexahydrobenz[c,d]indoles, being insoluble in base, precipitated, andthe precipitate was collected. Recrystallization of the precipitate frommethanol yielded about 3 g. of the dibromo derivative plus about 12.5 g.of the monobromo derivative and a considerable quantity of a crystalfraction which was a 1:1 mixture of starting material and monobromoderivative. (±)-5-Hydroxy-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indolethus formed melted at about 172° C. with decomposition. Twenty-four andone tenth grams (47% yield) of the 6-bromo derivative were obtained byrecrystallization of various fractions. The product as obtained stillcontained a small amount of the dibromo impurity.

A reaction mixture was prepared by dissolving 27.43 g. of(±)-5-hydroxy-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole in 100 ml.of pyridine and then adding in dropwise fashion 25 ml. of ethylchloroformate over a 20 minute period. About 0.5 g. of4-(N,N-dimethylamino)pyridine (DMAP) were added, and the resultingreaction mixture stirred at room temperature for about four hours. Thereaction mixture was then quenched by pouring into 1 liter of anice-water mixture. An oil which separated crystallized almostimmediately. The crystals were collected and washed thoroughly withwater. The dried ester amide was a faintly pink solid melting above 215°C. with decomposition; yield=40.48 g. (94%). Analysis indicated thatsome 6,8-dibromo compound continued as a contaminate

Forty and one tenth grams of(±)-1-ethoxycarbonyl-5-ethoxycarbonyloxy-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indolewere pyrolized in four different ten gram runs at 215-220° C. under anitrogen atmosphere. Each run required 25-30 minutes of heating. Thefour dark oily residues were combined, and the combined residues takenup in toluene. The toluene solution was chromatographed over silica. Oneand four tenths grams of starting material were recovered from fractionscontaining it but the mainproduct--1-ethoxycarbonyl-6-bromo-1,2,2a,3-tetrahydrobenz[c,d]indole--wasrecrystallized from a hexane/toluene solvent mixture containingpredominantly hexane to yield 19.36 g including a second crop, fromhexane alone. Yield=65% corrected for recovered starting material. Thecompound melted at 122-123° C.

Analysis Calculated: C, 54.56; H, 4.58,; N, 4.55; Br, 25.93.

Found: C, 54.59; H, 4.61; N, 4.41; Br, 25.84.

The unsaturated product from the above step was epoxidized as follows:

A solution of 7.5 g. of1-ethoxycarbonyl-6-bromo-1,2,2a,3-tetrahydrobenz[c,d]indole in 250 ml.of chloroform was cooled to about 0° C. with an ice/salt mixture. Sixgrams of 85% of m-chloroperbenzoic acid were added. The reaction mixturewas stirred at about 0° C. for one hour and was then kept atrefrigerator temperature overnight. The reaction mixture was washedsuccessively with 1N aqueous sodium hydroxide, saturated aqueous sodiumbisulfite, again with 1N aqueous sodium hydroxide and finally withbrine. The organic solution was dried, and the solvent removed in vacuo.The resulting solid residue was recrystallized from a toluene/hexanesolvent mixture. The first crop material obtained weighed 7.33 g. andmelted at 126-8° C.; total yield (2 crops)=98%.

Analysis Calculated: C, 51.87; H, 4.35; N, 4.32; Br, 24.65.

Found: C, 51.83; H, 11.33; N, 4.16; Br, 24.31.

A solution of 7.5 g. of1-ethoxycarbonyl-4,5-epoxy-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indoleobtained as above in 50 ml. of benzene was added slowly to a refluxingsolution of 1 g. of zinc iodide in 450 ml. of benzene which had beendried by distilling off 50 ml. of the benzene-water azeotrope. Refluxunder a nitrogen atmosphere was continued for one hour after theaddition had been completed. The reaction mixture was cooled. Thesupernate was decanted, and the decanted solution washed with water andthen with brine. The solution was dried and the solvent removedtherefrom in vacuo. The residue, comprising1-ethoxycarbonyl-4-oxo-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indoleformed in the above reaction, was crystallized from a toluene/hexanesolvent mixture. Five and thirty-six hundredths grams (71% yield) ofcrystalline product melting at 186-8° C. were obtained.

Analysis Calculated: C, 51.87; H, 4.35; N, 4.32; Br, 24.65.

Found: C, 51.75; H, 4.29; N, 4.50; Br, 24.80.

A reaction mixture was prepared from 14 g. of1-ethoxycarbonyl-4-oxo-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole,28.3 g. of n-propylamine, 4.9 ml. of glacial acetic acid and 300 ml. ofacetonitrile. The reaction mixture was stirred under a nitrogenatmosphere for about one hour. 3Å molecular sieves were added to absorbwater. Next, 5.6 g. of sodium cyanoborohydride were added followed by 14ml. of glacial acetic acid. This new reaction mixture was stirred for anadditional two hours at which time 7 ml. of glacial acetic acid wereadded. The reaction mixture was stirred for another two hours, andanother 7 ml. of glacial acetic acid added. Finally, the supernate wasdecanted from the molecular sieves, and the bulk of the volatileconstituents were removed in vacuo. The residual solution was pouredinto cold 2N aqueous sodium hdyroxide. The alkaline mixture wasextracted with methylene dichloride. The methylene dichloride extractwas washed with 0.5N aqueous sodium hydroxide and then with brine. Thesolvent was removed in vacuo. The resulting residue was dissolved in 1Naqueous hydrochloric acid to which methanol had been added. This acidicsolution was washed with ether, and the ether wash discarded. The acidicsolution was then made basic with 5N aqueous sodium hydroxide, and thenow insoluble (±)-1-ethoxycarbonyl-4-n-propylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole formed in the above reaction separatedand was extracted into methylene dichloride. The methylene dichlorideextract was separated, and the solvent removed therefrom to yield 16.7g. of an orange oil which was used in the next step without furtherpurification.

The above crude product was dissolved in 50 ml. of acetonitrile, 3 ml.of n-propyl iodide and 2 ml. of diisopropylethylamine. This solution wasallowed to remain in the dark for about three weeks. At this point intime, the solvent was removed under reduced pressure, and the residualmixture partitioned between ether and 0.5N aqueous sodium hydroxide. Theorganic layer was separated, and the aqueous alkaline layer extractedseveral times more with ether. The ether extracts were combined and thecombined extracts washed with brine and then dried. The ether wasremoved in vacuo to yield a residue. Xylene was added to the residue andremoved by evaporation to remove any remaining diisopropylethylamine.The unpurified residue slowly crystallized. The crystals were dissolvedin 20 ml. of methylene dichloride and 1 ml. of acetic anhydride wasadded thereto. After about an hour, the volatile constituents wereremoved in vacuo and the resulting residue dissolved in methylenedichloride. The methylene dichloride solution was stirred with aqueoussaturated sodium carbonate to remove any excess acetic anhydride. Themethylene dichloride layer was separated, and the methylene dichlorideremoved by evaporation. The residue was dissolved in a mixture of dilutehydrochloric acid and methanol. The resulting cloudy solution was washedwith ether and the ether was discarded. The acidic layer was then madebasic with which separated was extracted into methylene dichloride.Evaporation of the solvent gave a moist crystalline residue. The residuewas treated with hexane, and the hexane solution separated fromhexane-insoluble brown oil by decantation. The hexane was evaporated invacuo, and the residue chromatographed over 25 g. of silica gel usingethyl acetate as the eluant. Fractions containing the desired materialwere combined and the solvent removed therefrom in vacuo. The white,crystalline residue was transferred to a filter paper using coldisooctane. A total yield of 2.39 g. of(±)-1-ethoxycarbonyl-4-di-n-propylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indolewas obtained in two crops. m.p.=90-94° C.

Analysis Calculated: C, 58.68; H, 7.14; N, 6.84; Br, 19.52.

Found: C, 58.98; H, 6.88; N, 6.59; Br, 19.74.

Alternatively, a solution of 15.7 g. of the crude secondary amine.(±)-1-ethoxycarbonyl-4-n-propyl-amino-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indolein 80 ml. of pyridine was cooled to about 0° C. Sixteen ml. of propionicanhydride were added slowly. The solution was allowed to remain atambient temperature overnight. The bulk of the pyridine solvent wasremoved under vacuum, and the residual solution was stirred with anexcess of aqueous sodium carbonate for several hours to remove anyunreacted propionic anhydride and any by-product propionic acid. Theaqueous mixture was extracted with methylene dichloride, and themethylene dichloride extract separated and washed with 0.5M aqueoussodium hydroxide, 1N hydrochloric acid and brine. The organic solutionwas dried and the solvent removed therefrom in vacuo leaving a viscousoil. The oil was dissolved in 50 ml. of THF and this solution added overabout a 15 minute period to 85 ml. of 1M diborane in THF kept at about0° C. After the addition had been completed, the cooling bath wasremoved, and the reaction mixture heated to reflux temperature for about1.5 hours. The reaction mixture was then cooled to about 0° C. and 50ml. of methanol were added cautiously. The resulting reaction wasstirred overnight at room temperature. The methanol was removed invacuo. Additional methanol was added and again removed by evaporation.The resulting residue began to solidify. The semisolid residue waspartitioned between diethyl ether and 1M hydrochloric acid containingadded methanol. The solid which precipitated as a result of theseoperations was collected by filtration. The filtrate was made basic bythe addition of aqueous sodium hydroxide, and the alkaline mixtureextracted with methylene dichloride. The above ether layer, themethylene dichloride extract and the separated solid were combined andthe solvent evaporated. The residue was heated with wet DMSO, and thissolution was then diluted with water plus sufficient 1M aqueous sodiumhydroxide to maintain basic conditions. The alkaline mixture wasextracted with ether. The ether extract was in turn extracted with 1Mhydrochloric acid containing some methanol. The acidic extract was againmade basic, and the resulting alkaline mixture extracted with methylenedichloride. The methylene dichloride extracts were combined. Uponevaporation of the solvent, fifteen and fifty-nine hundredths grams ofcrude salmon colored compound were obtained. The solid was dissolved inethyl acetate and chromatographed over silica gel. Fractions containingthe desired material were combined and the solvent removed therefrom invacuo. Recrystallization of the resulting solid from isooctane gave(±)-1-ethoxycarbonyl-4-di-n-propylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indolemelting 87-9° C.; yield=14.8 g. (94%).

A solution of 1 g. of the above tertiary amine in 10 ml. of 6Nhydrochloric acid was heated to reflux temperature under nitrogenovernight. TLC indicated that only a trace of starting material remainedand that the chief product was(±)-4-di-n-propyl-amine-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole.The acidic solution was poured into dilute aqueous sodium hydroxide, andthe resulting alkaline layer extracted with methylene dichloride. Themethylene dichloride extract was separated and the separated extractwashed with brine and then dried. Evaporation of the solvent yielded aviscous oil which crystallized upon cooling. Recrystallization of theprecipitate from isooctane gave 0.683 g. (83% yield) of(±)-4-di-n-propylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indolemelting at about 62-3° C.

Analysis Calculated: C, 60.53; H, 7.47; N, 8.31; Br, 23.69.

Found: C, 60.71; H, 7.57; N, 8.30; Br, 23.78.

A run on a larger scale (14.8 g. of starting material) gave an 88% yieldof the desired hydrolysis product.

A suspension of 0.44 g. of N-chlorosuccinimide in 16 ml. of toluene waschilled to about 0° C. Three tenths ml. of dimethylsulfide were added.After 15 minutes, the reaction mixture was cooled in a dry ice-acetonebath to about -60° C. Six tenths grams of(±)-4-di-n-propylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole(prepared in Example A) and 2 ml. of toluene were added over a 15 minuteperiod. The reaction mixture was stirred at about -60° C. for about twohours at which point 0.8 ml. of triethylamine were added. The coolingbath was removed and stirring continued for about 21/2 hours at ambienttemperature. The reaction mixture was then poured into cold 1N aqueoussodium hydroxide and the now alkaline mixture extracted several timeswith toluene. The toluene extracts were combined, and the combinedextracts washed with brine and then dried. The solvent was removed andthe resulting residue chromatographed over 15 g. of Florosil using a 1:9ethyl acetate/toluene solvent mixture as the eluant. Fractionscontaining the desired product were combined and rechromatographed oversilica using the same eluant. Fractions containing the desired productwere again combined and the solvent evaporated therefrom to leave aslightly greenish oil. This oil was dissolved in about 20 ml. of pentaneand filtered to remove a colorless precipitate. The pentane was thenremoved by evaporation in vacuo. A yellow green oil weighing 0.303 g.(51% yield) was obtained comprising(±)-4-di-n-propylamino-6-bromo-1,3,4,5-tetrahydrobenz[c,d]indole formedin the above oxidation. The product crystallized upon standing;m.p.=72-3° C.

Analysis Calculated: C, 60.90; H, 6.91; N, 8.36; Br, 23.83.

Found: C, 60.77; H, 6.87; N, 8.28; Br, 23.61.

Alternatively, a solution of 1 g. of(±)-4-di-n-propylamino-6-bromo-1,2,2a,3,4,5-hexahydrobenz[c,d]indole and50 ml. of hexane was prepared. Four grams of activated manganese dioxidewere added and the resulting suspension sonicated (50-55 KHz) under anitrogen atmosphere for about one hour. TLC at this point indicatedalmost no starting material remaining. The reaction mixture was suctionfiltered, and the precipitate of magnese dioxide obtained was thoroughlywashed with fresh hexane. The hexane was removed from the filtrate andthe resulting residue chromatographed as before. Fractions containingthe desired indole were combined and the solvent removed by evaporation.Recrystallization of the resulting residue from isooctane yielded 0.62g. (62% yield) of(±)-4-di-n-propylamino-6-bromo-1,3,4,5-tetrahydrobenz[c,d]indole meltingat 73-4° C.

A solution of sodium methylate was prepared by dissolving 0.276 g. ofsodium metal in 3 ml. of methanol. Ten ml. of DMF were addded followedby 0.3 g. of CuI. 0.20 g. of(±)-4-di-n-propylamino-6-bromo-1,3,4,5-tetrahydrobenz[c,d]indole wereadded to the resulting suspension. The reaction mixture was heated atabout 130° C under N₂ for about 5 hours. The reaction mixture wasfiltered, and the filter cake washed thoroughly with DMF. Cold water wasadded to the filtrate. The aqueous layer was extracted three times withether. The combined ether extracts were washed with brine and dried.Removal of the ether in vacuo left a residue which was chromatographedover SiO₂ using 1:1 ethyl acetate/toluene as the eluant. Late fractionscontaining the desired 6-methoxy derivative were combined and thesolvent removed in vacuo. The viscous oily product was seeded withpreviously obtained crystals of the 6-methoxy derivative.Recrystallization from isooctane yielded(±)-4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indolemelting at 87-9° C.; yield =80%

Analysis Calculated: C, 75.48; H, 9.15; N, 9.78;

Found: C, 75.64; H, 9.25; N, 9.62.

The central serotonergic action of drugs according to IV above wasdemonstrated in two ways. The first method was to show inhibition oftritiated serotonin uptake according to the following protocol. (Weakinhibition of tritiated spiperone uptake was also determined.) Several(±)-4-di-n-propylamino-6-substituted-1,3,4,5-tetrahydroindoles plus thecorresponding drug from Bach-Kornfeld United U.S. Pat. No. 4,110,339lacking a C-6 substituent were tested.

Brain tissue was obtained from 150-200 g. male Wistar rats. The cerebralcortex was dissected out and then homogenized and centrifuged accordingto the method described by Nelson and coworkers, Mol. Pharmacol., 14,983-995 (1978), using preincubation in buffer without added monoamineoxidase inhibitor in order to eliminate endogenous serotonin. Forreceptor binding, each sample contained 300-400 μg. of membrane proteinand 10 μM pargyline in addition to the ³ H-ligand in 1 ml. of 0.05 MTris buffer, pH=7.4. The assay of serotonin binding was done followingthe method of Bennett and Snyder, Mol. Pharmacol., 12, 373-389 (1976),and that for tritiated spiperone according to Peroutka and Snyder, Mol.Pharmacol., 16, 687-699 (1979). The samples were incubated for 15minutes at 37° and were then filtered through GF/C glass fiber filterpads using a Brandel M-24 cell harvester modified for receptor binding.After two 5 ml. rinses, the filter discs were put into scintillationvials and counted in 10 ml. of Amersham PCS scintillation fluid.Nonspecific binding of ³ H-serotonin (³ H-5HT) was determined in thepresence of 10⁻⁵ M serotonin and of ³ H-spiperone in the presence of10⁻⁶ M LSD. Specific binding was calculated as the difference betweentotal binding with no added nonradioactive compound and the nonspecificbinding. IC₅₀ values were determined where the IC₅₀ is the amount ofsubstance causing 50 percent inhibition of the specific binding using10-12 concentrations in the range of 10⁻⁹ to 10⁻⁴ M. The concentrationsof 3H-ligands were: serotonin (Amersham, 11 Ci/mmol), 2-3 nM; LSD(Amersham, 1.8 Ci/mmol), 1.8-2.6 nM; spiperone (Amersham, 20 Ci/mmol),0.6-0.7 nM.

The results obtained, are set forth in Table 1.

                  TABLE 1                                                         ______________________________________                                        RECEPTOR BINDING                                                                                .sup.3 H-Ligand-IC.sub.50 *                                 Name of Compound    .sup.3 H-5HT                                                                           .sup.3 H-SPIP                                    ______________________________________                                        (±)-4-dimethylamino-6-                                                                         70       1490                                             methoxy-1,3,4,5-tetra-                                                        hydrobenz[c,d]indole                                                          (±)-4-di-n-propylamino-6-                                                                      50       950                                              methoxy-1,3,4,5-tetrahydro-                                                   benz[c,d]indole                                                               (±)-4-dimethylamino-                                                                           120      730                                              1,3,4,5-tetrahydrobenz-                                                       [c,d]indole                                                                   ______________________________________                                         *Values are in nanomoles of inhibitor.                                   

Secondly, as a measure of central serotonin agonist activity, thedecrease of serotonin metabolites in brain was measured. Also themeasure of dopamine agonist activity was indicated by changes indopamine metabolites.

The following protocol was employed. 150-200 g. Wistar rats were given0.3 mg/kg subcutaneously of(±)-4-di-n-propylamino-6-substituted-1,3,4,5-tetrahydrobenz[c,d]indole.Then, 60 minutes later each rat was decapitated and the hypothalamus andstriatum were dissected out and extracted. The amounts of homovanillicacid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatumand of 5-hydroxyindoleacetic acid (5HIAA) in the hypothalamus weremeasured by high-performance liquid chromatography, usingelectrochemical detection. Serum corticosteroids were also measured.Table 2 gives the results of this experiment. In the table, columns 1and 2 give the substitution pattern in the compounds of formula IV,columns 3-5, the 5HT or dopamine metabolite concentrations, and column6, the serum corticosteroids.

                                      TABLE 2                                     __________________________________________________________________________             5HIAA In                                                                              Dopamine Metabolites                                                                       Serum                                                    Hypothalamus                                                                          In Striatum, NMoles/G                                                                      Corticosterone                                  X  R.sup.1 and R.sup.2                                                                 NMoles/G                                                                              DOPAC HVA    MCG/100 ML                                      __________________________________________________________________________    OMe                                                                              di-nPr                                                                              1.51 ± .05*                                                                        4.61 ± .10*                                                                       2.43 ± .18*                                                                      48 ± 2*                                      OMe                                                                              di-Me 1.69 ± .07*                                                                        7.15 ± .23*                                                                      4.68 ± .21                                                                        41 ± 4*                                      (control)                                                                              2.59 ± .11                                                                         5.58 ± .38                                                                       4.24 ± .27                                                                        7 ± 1                                        __________________________________________________________________________     Compounds were injected at 0.3 mg/kg s.c. 1 hour before rats were killed.     *statistically significant                                               

Thirdly, as a measure of central serotonin agonist activity, the testrats received(±)-4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole. Thedecrease of serotonin turnover in brain was measured as a function of5-hydroxytryptophane (5-HTP) accumulation when the decarboxylation of5-HTP is blocked by m-hydroxybenzylhydrazine, using the above protocol,except that thirty minutes after injection of the drug,m-hydroxybenzylhydrazine was injected at 100 mg./kg. i.p. Then, 40minutes later each rat was decapitated, the hypothalamus dissected outand extracted. The amount of 5-HTP in each extract were measured byhigh-performance liquid chromatography, using electrochemical detection.In normal rats, 5-HTP brain levels are so low as to be virtuallyundetectable. Thus, the control group received the same dose ofm-hydroxybenzylhydrazine as the test rats but no drug. Table 3 gives theresults of this experiment.

                  TABLE 3                                                         ______________________________________                                        UPTAKE INHIBITION                                                                             5HTP Level in Nanomoles                                       Dose of Drug Mg./Kg.                                                                          of Hypothalamus ± S.E.                                     ______________________________________                                        0               1.81 ± 0.11                                                0.01            1.85 ± 0.06                                                0.03            1.72 ± 0.07                                                0.10             1.16 ± 0.05*                                              0.30             0.97 ± 0.03*                                              ______________________________________                                         *Significant difference from zero dose group (P < .05).                  

The above results indicate that certain dose levels of(±)-4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indolesignificantly decreased 5HTP accumulation, thus indicating centralserotonin agonist activity at those dosage levels or at higher dosagelevels.

Drugs which have central serotonin agonist activity are useful asantidepressants. The compounds of formula IV which have such centralserotonergic activity to a marked degree with minimal agonist orantagonist actions toward NE or dopamine should be particularly usefulin that their use would not be accompanied by side effects common topresently marketed antidepressants, particularly the antimuscariniceffect. Several of the marketed antidepressants are also monamineoxidase inhibitors, a nonspecific amine oxidase linked with metabolicdegradation of both catecholamines and serotonin, which activity is alsolacking in the drugs of formula IV.

The novel drugs of formula IV can be administered parenterally as anisotonic solution of a pharmaceutically acceptable salt. Preferably,however, the drugs are administered orally. For such route ofadministration, the drug is mixed with one or more pharmaceuticalexcipients and loaded into empty telescoping gelatin capsules orcompressed into tablets, each tablet or capsule to contain a unitantidepressant dosage of the drug.

I claim:
 1. An intermediate of the formula ##STR8## wherein R¹ and R² are individually methyl, ethyl, n-propyl or allyl, and X is OC₁₋₃ alkyl, and pharmaceutically acceptable salts thereof.
 2. A compound according to claim 1 in which X is OCH₃.
 3. A compound according to claim 1 in which R¹ and R² are the same C₁₋₃ alkyl group.
 4. A compound according to claim 3 in which R¹ and R² are both n-propyl.
 5. A compound according to claim 1, said compound being (±)-4-(di-n-propyl)amino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole.
 6. A compound of the formula ##STR9## wherein X is OC₁₋₃ alkyl, R¹ and R² individually methyl, ethyl, n-propyl or allyl, and Z is a carboxylic or sulfonic acyl group.
 7. A compound according to claim 6 in which the acyl protecting group Z is benzoyl.
 8. A compound according to claim 6 in which R¹ and R² are both n-propyl.
 9. A compound according to claim 6 in which X is OCH₃.
 10. A compound according to claim 6, said compound being (±)-1-benzoyl-4-(di-n-propyl)amino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole.
 11. A compound of the formula ##STR10## wherein X is OC₁₋₃ alkyl, and Z is a carboxylic or sulfonic acyl protecting group.
 12. A compound according to claim 11 in which X is OCH₃.
 13. A compound according to claim 12, said compound being (+)-4-amino-6-methoxy-1,2,2a,3,4,5-hexahydrobenz[c,d]indole. 